Neural circuits implicated in drug conditioning, craving, and relapse overlap with those involved in natural reward. Recently, the orexin/hypocretin (Orx/Hcrt) system has been identified to regulate a range of physiological processes, including feeding, energy metabolism, and arousal, and has been shown to be recruited by drugs of abuse. Orx/Hcrt neurons are predominantly located in the lateral hypothalamus (LH), and accumulating evidence indicates an important role for these neurons in drug addiction. These Orx/Hcrt neurons project to the paraventricular nucleus of the thalamus (PVT), a region that has been identified as a way- station that receives projections from the LH, processes information, and then modulates the mesolimbic and extrahypothalamic stress systems. While not thought to be part of the cocaine-seeking circuitry, evidence implicates the PVT in the modulation of reward function in general and drug-directed behavior in particular. Importantly, a correlation between cocaine-seeking behavior and activation of the PVT has been detected, but not in the case of natural reward-seeking behavior. This suggests that cocaine dysregulates the neurotransmission within the PVT. Capitalizing on our findings, we hypothesize that following repeated cocaine use, the Orx/Hcrt system acquires a preferential role in mediating drug of abuse seeking vs. natural reward seeking. This proposal is designed to study the neurobiological basis of chronic vulnerability to relapse by focusing on Orx/Hcrt transmission in the PVT as a novel neural substrate that may be responsible for the distinctly compulsive nature of cocaine seeking as opposed to behavior motivated by natural rewards essential for survival, well being, and healthy hedonic pursuits. Specifically, this proposal will (i) behaviorally characterize the specific implication of the PVT in cocaine seeking, (ii) investigate cocaine-induced neuroplastic changes within Orx/Hcrt transmission and (iii) investigate the effects of dysregulated Orx/Hcrt-PVT transmission on the mesolimbic system. PUBLIC HEALTH RELEVANCE: Currently, the available therapeutic approaches fail to completely treat and address the compulsive nature of drug seeking and drug taking associated with addiction. Preliminary evidence indicates that dysfunctional orexin/hypocretin transmission contributes to cocaine seeking vs. natural reward seeking. This project is likely to highlight a previously unrecognized mechanism in the etiology of cocaine dependence and may identify novel therapeutic targets for drug addiction.